Mechanism and Synergy of gamma-Secretase Modulators

 描述（由申请人提供）：本提案的总体目标是阐明不同类别的下一代γ-分泌酶调节剂（GSM）的作用机制，确定其协同效应，并将其应用于检查Aβ42、Aβ38和Aβ37在淀粉样蛋白病理学、突触可塑性以及学习和记忆中的作用。GSMs的开发可抑制γ-分泌酶产生Aβ42的活性，但不影响APP的整体加工和其他底物的裂解，已成为AD治疗的一种有前景的策略。这些临床候选药物的开发进展取决于对药物-靶标相互作用的更深入理解。为此，我们建议绘制γ-分泌酶复合物中酸性GSMs的结合位点，并研究γ-分泌酶调节的结构基础。此外，我们将确定γ-分泌酶活性位点与咪唑基GSM结合位点之间的协同作用机制。最后，我们将研究两类GSM在细胞和动物模型中的协同作用，重点是安全性，突触可塑性和学习记忆。拟议的研究将为GSM对γ-分泌酶的调节、Aβ在疾病中的功能和新的治疗策略提供机制见解，塑造我们对GSM选择性的理解，并提高我们设计有效治疗的能力。

 DESCRIPTION (provided by applicant): The overall objectives of this proposal are to elucidate the mechanism of action of different classes of next generation γ-secretase modulators (GSMs), to determine their synergistic effect, and to apply them in examining the role of Aβ42, Aβ38 and Aβ37 in amyloid pathology, synaptic plasticity and learning and memory. The development of GSMs that suppress γ-secretase activity for Aβ42 production and yet do not affect overall APP processing and cleavages of other substrates has emerged as a promising strategy for AD therapy. Progress in the development of these clinical candidates depends on a deeper understanding of the drug-target interactions. To this end we propose to map the binding site of acid GSMs within the γ-secretase complex and to investigate the structural basis of γ-secretase modulation. Additionally, we will determine the mechanism of cooperatively between the γ-secretase active site and the imidazole based GSM binding site(s). Finally, we will examine the synergistic effect of two classes of GSMs in cellular and animal models with a focus on safety, synaptic plasticity and learning and memory. The proposed research will provide mechanistic insights into GSM modulation of γ-secretase, the function of Aβ in disease and new therapeutic strategies, shaping our understanding of GSM selectivity and advancing our ability to design effective treatment.